tbuckley/cabot-search huggingface dataset:
Trends in Rates of Opioid Agonist Treatment and Opioid-Related Deaths for Youths in Ontario, Canada, 2013-2021
Authors: Tea Rosic, Gillian Kolla, Pamela Leece, Sophie Kitchen, Tara Gomes
Journal: JAMA Network Open (2023)

Importance Data suggest that the opioid crisis in North America has recently been reflected in opioid-related mortality among youths. Despite recommendation for its use, youths encounter barriers to accessing OAT, including stigma, burden of witnessed dosing, and lack of availability of youth-oriented services and prescribers comfortable treating this population. Objective To compare rates of opioid agonist treatment (OAT) and opioid-related mortality between youths aged 15 to 24 years and adults aged 25 to 44 years in Ontario, Canada, over time. Design, Setting, and Participants This cross-sectional analysis of rates of OAT and opioid-related deaths between 2013 and 2021 used data obtained from the Ontario Drug Policy Research Network, Public Health Ontario, and Statistics Canada. Individuals included in the analysis were aged 15 to 44 years and residing in Ontario, the most populous province in Canada. Exposures Youths aged 15 to 24 years compared with adults aged 25 to 44 years. Main Outcomes and Measures OAT (methadone, buprenorphine, and slow-release oral morphine) per 1000 population and opioid-related deaths per 100 000 population. Results Between 2013 and 2021, 1021 youths aged 15 to 24 years died from opioid toxicity; 710 were male (69.5%). In the final year of the study period, 225 youths (146 male [64.9%]) died from opioid toxicity, and 2717 (1494 male [55.0%]) were dispensed OAT. Over the study period, the rate of opioid-related deaths among youths in Ontario increased 369.2% from 2.6 to 12.2 per 100 000 population (48 to 225 total deaths) and the rate of OAT use decreased 55.9% from 3.4 to 1.5 per 1000 (6236 to 2717 individuals). For adults aged 25 to 44 years, the rate of opioid-related deaths increased 371.8% from 7.8 to 36.8 per 100 000 (283 to 1502 deaths), and the rate of OAT increased 27.8% from 7.9 to 10.1 per 1000 population (28 667 to 41 200 individuals). Trends for youths and adults persisted across both sexes. Conclusions and Relevance The findings of this study suggest that opioid-related deaths are increasing among youths while OAT use is paradoxically declining. The reasons for these observed trends require further investigation, including a consideration of changing trends in opioid use and opioid use disorder among youths, barriers to OAT, and opportunities to optimize care and reduce harms for youths who use substances.
Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment
Authors: Dhanya K. Nambiar, Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Jeanette Koong, Rie von Eyben, Sylvia Plevritis, Lingyin Li, Amato Giaccia, Edgar Engleman, Quynh Thu Le
Journal: Cancer Research (2023)

Abstract The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a premetastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from premetastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the premetastatic compartment. Gal1 promoted MDSC accumulation in the premetastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing stimulator of interferon gene (STING) protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected protumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous-positive regulator of STING in advanced-stage cancers. Significance: Galectin-1 increases STING stability in cancer cells that activates NF-κB signaling and CXCL2 expression to promote MDSC trafficking, which stimulates the generation of a premetastatic niche and facilitates metastatic progression.
Near‐Infrared Light‐Enhanced Generation of Hydroxyl Radical for Cancer Immunotherapy
Authors: Qianqian Zhang, Yang Li, Chunhuan Jiang, Wenbo Sun, Jingwei Tao, Lehui Lu
Journal: Advanced Healthcare Materials (2023)

Hydroxyl radical (• OH) as a highly oxidizing reactive oxygen species can induce immunogenic cell death (ICD) in cancer treatment. However, high-efficiency cancer immunotherapy is still a huge challenge due to the low • OH generation efficiency in the tumor microenvironment, resulting in insufficient immunogenicity and the poor immune response. Here, a near-infrared (NIR) light-enhanced • OH generation strategy is developed for cancer immunotherapy by using a copper-based metal-organic framework (Cu-DBC) nanoplatform. With this strategy, the generation efficiency of • OH under NIR irradiation is increased 7.34 times than that without NIR irradiation, which induces robust ICD and immune response, thus leading to primary tumor elimination and the inhibition of distant tumor growth and tumor lung metastasis. Experimental results show that Cu-DBC can induce • OH boosting through photothermal (PT)-enhanced Cu-catalytic Fenton-like reaction and photocatalytic electron transfer under NIR light irradiation to amplify tumor ICD for immunotherapy.
Intraregional hospital outbreak of OXA-244-producing Escherichia coli ST38 in Norway, 2020
Authors: Paul Christoffer Lindemann, Torunn Pedersen, Dorthea Hagen Oma, Jessin Janice, Fredrik Grøvan, Ghantous Milad Chedid, Liv Jorunn Hafne, Ellen H. Josefsen, Oliver Kacelnik, Arnfinn Sundsfjord, Ørjan Samuelsen
Journal: Eurosurveillance (2023)

Infections with OXA-244-carbapenemase-producing Escherichia coli with sequence type (ST)38 have recently increased in Europe. Due to its low-level activity against carbapenems, OXA-244 can be difficult to detect. Previous assessments have not revealed a clear source and route of transmission for OXA-244-producing E. coli , but there are indications of non-healthcare related sources and community spread. Here we report a hospital-associated outbreak of OXA-244-producing E. coli ST38 involving three hospitals in Western Norway in 2020. The outbreak occurred over a 5-month period and included 12 cases identified through clinical (n = 6) and screening (n = 6) samples. The transmission chain was unclear; cases were identified in several wards and there was no clear overlap of patient stay. However, all patients had been admitted to the same tertiary hospital in the region, where screening revealed an outbreak in one ward (one clinical case and five screening cases). Outbreak control measures were instigated including contact tracing, isolation, and screening; no further cases were identified in 2021. This outbreak adds another dimension to the spread of OXA-244-producing E. coli ST38, illustrating this clone’s ability to establish itself in the healthcare setting. Awareness of challenges concerning OXA-244-producing E. coli diagnostic is important to prevent further spread.
p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricle Pressure Overload
Authors: Xiaoyi Liu, Ryan M. Burke, Janet K. Lighthouse, Cameron D. Baker, Ronald A. Dirkx, Brian Kang, Yashoswini Chakraborty, Deanne M. Mickelsen, Jennifer J. Twardowski, Stephano S. Mello, John M. Ashton, Eric M. Small
Journal: Circulation Research (2023)

Cardiomyopathy is characterized by the pathological accumulation of resident cardiac fibroblasts that deposit ECM (extracellular matrix) and generate a fibrotic scar. However, the mechanisms that control the timing and extent of cardiac fibroblast proliferation and ECM production are not known, hampering the development of antifibrotic strategies to prevent heart failure.
Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics
Authors: Ryan M Marquardt, Dinh Nam Tran, Bruce A Lessey, Md Saidur Rahman, Jae-Wook Jeong
Journal: Endocrine Reviews (2023)

Abstract Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying an epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in controlling epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation, with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis and resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.
Extracellular Vesicle–Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart
Authors: Xisheng Li, Sabrina La Salvia, Yaxuan Liang, Marta Adamiak, Erik Kohlbrenner, Dongtak Jeong, Elena Chepurko, Delaine Ceholski, Estrella Lopez-Gordo, Seonghun Yoon, Prabhu Mathiyalagan, Neha Agarwal, Divya Jha, Shweta Lodha, George Daaboul, Anh Phan, Nikhil Raisinghani, Shihong Zhang, Lior Zangi, Edgar Gonzalez-Kozlova, Nicole Dubois, Navneet Dogra, Roger J. Hajjar, Susmita Sahoo
Journal: Circulation (2023)

Adeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use is preexisting neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction, and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance.We developed a 2-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs. We compared the gene delivery and therapeutic efficacy of EV-AAVs with an equal titer of free AAVs in the presence of NAbs, both in vitro and in vivo. In addition, we investigated the mechanism of EV-AAV uptake in human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and mouse models in vivo using a combination of biochemical techniques, flow cytometry, and immunofluorescence imaging.Using cardiotropic AAV serotypes 6 and 9 and several reporter constructs, we demonstrated that EV-AAVs deliver significantly higher quantities of genes than AAVs in the presence of NAbs, both to human left ventricular and human induced pluripotent stem cell-derived cardiomyocytes in vitro and to mouse hearts in vivo. Intramyocardial delivery of EV-AAV9-sarcoplasmic reticulum calcium ATPase 2a to infarcted hearts in preimmunized mice significantly improved ejection fraction and fractional shortening compared with AAV9-sarcoplasmic reticulum calcium ATPase 2a delivery. These data validated NAb evasion by and therapeutic efficacy of EV-AAV9 vectors. Trafficking studies using human induced pluripotent stem cell-derived cells in vitro and mouse hearts in vivo showed significantly higher expression of EV-AAV6/9-delivered genes in cardiomyocytes compared with noncardiomyocytes, even with comparable cellular uptake. Using cellular subfraction analyses and pH-sensitive dyes, we discovered that EV-AAVs were internalized into acidic endosomal compartments of cardiomyocytes for releasing and acidifying AAVs for their nuclear uptake.Together, using 5 different in vitro and in vivo model systems, we demonstrate significantly higher potency and therapeutic efficacy of EV-AAV vectors compared with free AAVs in the presence of NAbs. These results establish the potential of EV-AAV vectors as a gene delivery tool to treat heart failure.
Variations in Physician Telemedicine Provision
Authors: Nate C. Apathy, Ram A. Dixit, Christian L. Boxley, Katharine T. Adams, Ethan Booker, Raj M. Ratwani
Journal: JAMA Network Open (2023)

This cross-sectional study assesses variation in the provision of telemedicine services among primary care physicians and quantifies the extent to which this variation may be explained by the individual physician vs temporal, patient, or visit factors.
Trends in Psychological Distress Among Adults in England, 2020-2022
Authors: Sarah E. Jackson, Jamie Brown, Lion Shahab, Ann McNeill, Marcus R. Munafò, Leonie Brose
Journal: JAMA Network Open (2023)

Importance In the last 3 years, people in England have lived through a pandemic and cost-of-living and health care crises, all of which may have contributed to worsening mental health in the population. Objective To estimate trends in psychological distress among adults over this period and to examine differences by key potential moderators. Design, Setting, and Participants A monthly cross-sectional, nationally representative household survey of adults aged 18 years or older was conducted in England between April 2020 and December 2022. Main Outcomes and Measures Past-month distress was assessed with the Kessler Psychological Distress Scale. Time trends in any distress (moderate to severe, scores ≥5) and severe distress (scores ≥13) were modeled, and interactions with age, gender, occupational social grade, children in the household, smoking status, and drinking risk status were tested. Results Data were collected from 51 861 adults (weighted mean [SD] age, 48.6 [18.5] years; 26 609 women [51.3%]). There was little overall change in the proportion of respondents reporting any distress (from 34.5% to 32.0%; prevalence ratio [PR], 0.93; 95% CI, 0.87-0.99), but the proportion reporting severe distress increased by 46%, from 5.7% to 8.3% (PR, 1.46; 95% CI, 1.21-1.76). Although trends differed by sociodemographic characteristics, smoking, and drinking, the increase in severe distress was observed across all subgroups (with PR estimates ranging from 1.17 to 2.16), with the exception of those aged 65 years and older (PR, 0.79; 95% CI, 0.43-1.38); the increase was particularly pronounced since late 2021 among those younger than 25 years (increasing from 13.6% in December 2021 to 20.2% in December 2022). Conclusions and Relevance In this survey study of adults in England, the proportion reporting any psychological distress was similar in December 2022 to that in April 2020 (an extremely difficult and uncertain moment of the COVID-19 pandemic), but the proportion reporting severe distress was 46% higher. These findings provide evidence of a growing mental health crisis in England and underscore an urgent need to address its cause and to adequately fund mental health services.
Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability
Authors: Suet Yen Chong, Xiaoyuan Wang, Louis van Bloois, Chenyuan Huang, Nilofer Sayed Syeda, Sitong Zhang, Hui Jun Ting, Vaarsha Nair, Yuanzhe Lin, Charles Kang Liang Lou, Ayca Altay Benetti, Xiaodong Yu, Nicole Jia Ying Lim, Michelle Siying Tan, Hwee Ying Lim, Sheau Yng Lim, Chung Hwee Thiam, Wen Donq Looi, Olga Zharkova, Nicholas W.S. Chew, Cheng Han Ng, Glenn Kunnath Bonney, Mark Muthiah, Xiaoyuan Chen, Giorgia Pastorin, A. Mark Richards, Veronique Angeli, Gert Storm, Jiong-Wei Wang
Journal: Journal of Controlled Release (2023)
Effect of Risk-Stratified Care on Disability Among Adults With Low Back Pain Treated in the Military Health System
Authors: Daniel I. Rhon, Tina A. Greenlee, Emily Poehlein, Jason M. Beneciuk, Cynthia L. Green, Ben R. Hando, John D. Childs, Steven Z. George
Journal: JAMA Network Open (2023)

Importance Tailored treatments for low back pain (LBP) based on stratifying risk for poor prognosis have emerged as a promising approach to improve quality of care, but they have not been validated in trials at the level of individual randomization in US health systems. Objective To assess the clinical effectiveness of risk-stratified vs usual care on disability at 1 year among patients with LBP. Design, Setting, and Participants This parallel-group randomized clinical trial enrolled adults (ages 18-50 years) seeking care for LBP with any duration in primary care clinics within the Military Health System from April 2017 to February 2020. Data analysis was conducted from January to December 2022. Interventions Risk-stratified care, in which participants received physiotherapy treatment tailored for their risk category (low, medium, or high), or usual care, in which care was determined by participants’ general practitioners and may have included a referral to physiotherapy. Main Outcomes and Measures The primary outcome was the Roland Morris Disability Questionnaire (RMDQ) score at 1 year, with planned secondary outcomes of Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference (PI) and Physical Function (PF) scores. Raw downstream health care utilization was also reported within each group. Results Analysis included 270 participants (99 [34.1%] female participants; mean [SD] age, 34.1 [8.5] years). Only 21 patients (7.2%) were classified as high risk. Neither group was superior on the RMDQ (least squares [LS] mean ratio of risk-stratified vs usual care: 1.00; 95% CI, 0.80 to 1.26), the PROMIS PI (LS mean difference, −0.75 points; 95% CI −2.61 to 1.11 points), or the PROMIS PF (LS mean difference, 0.05 points; 95% CI, −1.66 to 1.76 points). Conclusions and Relevance In this randomized clinical trial, using risk stratification to categorize and provide tailored treatment for patients with LBP did not result in better outcomes at 1 year compared with usual care. Trial Registration ClinicalTrials.gov Identifier: NCT03127826
Psychiatric Boarding Patterns Among Publicly Insured Youths Evaluated by Mobile Crisis Teams Before and During the COVID-19 Pandemic
Authors: Carolina-Nicole Herrera, Rachel Oblath, Alison Duncan
Journal: JAMA Network Open (2023)

Importance Psychiatric boarding occurs when patients needing intensive psychiatric services who are already under clinical supervision experience delays in their admission to psychiatric facilities. Initial reports have suggested that the US had a psychiatric boarding crisis during the COVID-19 pandemic; however, little is known about the consequences of this crisis for publicly insured youths. Objective To estimate pandemic-associated changes in psychiatric boarding rates and discharge modalities for people aged 4 to 20 years who accessed psychiatric emergency services (PES) through a mobile crisis team (MCT) evaluation and were covered by Medicaid or health safety net programs. Design, Setting, and Participants This retrospective cross-sectional study used data from the MCT encounters of a multichannel PES program in Massachusetts. A total of 7625 MCT-initiated PES encounters with publicly insured youths who lived in Massachusetts between January 1, 2018, and August 31, 2021, were assessed. Main Outcomes and Measures Encounter-level outcomes (psychiatric boarding status, repeat visits, and discharge disposition) during a prepandemic period (January 1, 2018, to March 9, 2020) were compared with outcomes during a pandemic period (March 10, 2020, to August 31, 2021). Descriptive statistics and multivariate regression analysis were used. Results Among 7625 MCT-initiated PES encounters, the mean (SD) age of publicly insured youths was 13.6 (3.7) years; most youths identified as male (3656 [47.9%]), were of Black race (2725 [35.7%]) or Hispanic ethnicity (2708 [35.5%]), and spoke English (6941 [91.0%]). During the pandemic period, the mean monthly boarding encounter rate was 25.3 percentage points higher than the prepandemic period. After adjustment for covariates, the odds of an encounter resulting in boarding doubled during the pandemic (adjusted odds ratio [AOR], 2.03; 95% CI, 1.82-2.26; P &amp;amp;lt; .001), and boarding youths were 64% less likely to be discharged to inpatient psychiatric care (AOR, 0.36; 95% CI, 0.31-0.43; P &amp;amp;lt; .001). Publicly insured youths who boarded during the pandemic had significantly higher rates of 30-day readmissions (incidence rate ratio, 2.17; 95% CI, 1.88-2.50; P &amp;amp;lt; .001). Boarding encounters during the pandemic were significantly less likely to end in discharge to inpatient psychiatric units (AOR, 0.36; 95% CI, 0.31-0.43; P &amp;amp;lt; .001) or community-based acute treatment facilities (AOR, 0.70; 95% CI, 0.55-0.90; P = .005). Conclusions and Relevance In this cross-sectional study, publicly insured youths were more likely to experience psychiatric boarding during the COVID-19 pandemic and, if boarding, were less likely to transfer to a 24-hour level of care. These findings suggest that psychiatric service programs for youths were not prepared to support the levels of acuity and demand that emerged from the pandemic.